Mycobacterial F₁F₀ ATP synthase (ATP synthase)

Mycobacterial F₁F₀ ATP synthase is a multi-subunit enzyme complex essential for the energy metabolism of mycobacteria, including Mycobacterium tuberculosis [1, 4]. It functions as the primary catalyst for adenosine triphosphate (ATP) synthesis via oxidative phosphorylation, utilizing the proton motive force generated by the electron transport chain [2, 5]. The enzyme consists of a membrane-embedded F₀ sector involved in proton translocation and a cytoplasmic F₁ sector where ATP is synthesized from ADP and inorganic phosphate [5, 12]. This target is particularly vital because mycobacteria rely on it for survival during both active growth and latent phases of infection [4, 12]. The clinical significance of this target was established with the approval of bedaquiline, a diarylquinoline that selectively binds to the c-ring of the mycobacterial F₀ sector [6, 9]. This interaction inhibits the rotation of the enzyme, leading to a rapid depletion of ATP and subsequent bacterial death [9, 13]. While bedaquiline is a cornerstone in treating multidrug-resistant tuberculosis, its use is associated with safety concerns such as QTc prolongation and potential hepatotoxicity [1, 11]. Research continues into next-generation inhibitors like TBAJ-876, which aim to provide improved safety profiles and broader efficacy against non-tuberculous mycobacteria [2, 6].

Other names

F-type ATPaseH+-transporting ATP synthaseMycobacterial F-ATP synthaseF1F0-type ATP synthaseATP synthase complex

Inhibition of the c-ring rotation within the F0 sector, which halts the catalytic activity of the F1 sector and depletes cellular ATP levels.